Determining if the Developmental Origin of Cardiac Fibroblasts Determines the Fate of Activation in Adult-Onset Hypertension

Abstract

Heart disease remains a leading cause of morbidity and mortality worldwide, responsible for 1 in5 deaths, with cardiac fibrosis playing a critical role in heart failure progression [13, 18, 17]. Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition and tissue stiffening, impairs cardiac function, reducing contractility and increasing the risk of arrhythmias [13, 17]. Resident cardiac fibroblasts, originating from epicardial and endothelial progenitors, are essential regulators of fibrosis [7, 9, 10]. Periostin expression is canonically known as a marker of the activated fibroblast state in disease, but it is also upregulated during postnatal day 1 through postnatal day 11 [6] in development. We hypothesize that a neonatal Periostin- expressing fibroblast population is poised to activate in adulthood when challenged with a profibrotic stimulus. Previous work in the Davis Lab has shown that fibroblasts retain intrinsic memory, where when exposed to injury they exhibit a heightened reactivity upon re-injury [1, 4, 10, 12]. However, it appears that there is not a new population that activates when challenged with a second fibrotic injury after a period of recovery (Figure 4B). To test this, we used genetic lineage tracing via a tamoxifen-inducible Cre model to label Periostin+ fibroblasts in neonatal mice during the first 9 days in the postnatal period, before challenging them with AngII/PE in adulthood to determine if they reactivate upon injury. Histological analysis of whole hearts confirmed treatment dependent ECM remodeling following injury. This thesis demonstrates that Postn-lineage derived fibroblasts are poised to activate and expand when responding to injury or stress. Currently, the postnatal role of Postn-lineage fibroblasts remains poorly understood however, this is important to understand fibrotic regression and how it depends on both ECM remodeling and the deactivation of Postn-lineage myofibroblasts during postnatal development. In the Davis Lab, this information can be utilized to understand the role this population of fibroblasts plays in wound healing for other models such as dilated cardiomyopathy and myocardial infarction. These insights may inform therapeutic strategies targeting Postn-lineage fibroblasts to reverse fibrosis and improve overall heart function.